Amyotrophic lateral sclerosis (ALS) is a devastating chronic neurodegenerative disease with minimally effective therapy. Our own efforts to develop meaningful therapies have focused upon neuroinflammation and the roles of the innate and adaptive immune systems in ALS patients. ALS neuropathology is marked by gliosis and infiltrating T-cells both in ALS patients and in mSOD1 transgenic animal models of inherited ALS. Although earlier studies were ambiguous as to whether this inflammation contributed to neuronal protection, neuronal injury, or was merely a late consequence of injury, it has recently become apparent that CD4+ T cells play an endogenous neuroprotective role in ALS. In mSOD1 mice bred with mice lacking functional T cells, or CD4+ T cells, motoneuron disease was accelerated, accompanied by increased levels of pro-inflammatory cytokines. Bone marrow transplants reconstituted these mice with functional T cells leading to prolonged survival and suppressed neurotoxicity. Another study using mSOD1 transgenic mice bred with different T cell deficient mice reached a similar conclusion, namely that T cells have the abilities to improve neurological function and life expectancy in mSOD1 mice. Our preliminary data suggest that mSOD1/RAG2-/- mice passively transferred with CD4+ T cells are neuroprotective but that CD4+ T cells obtained from mSOD1 mice are more beneficial than CD4+ T cells obtained from wild-type mice. These data establish that the ALS patient's own CD4+ T cells may be used for therapy and may provide the opportunity for therapeutic intervention in ALS. Thus, we hypothesize that CD4+ T cells, or subpopulations of CD4+ T cells, are a clinically relevant and beneficial therapy in mSOD1 mice, and may provide clinical benefit in ALS. The 1st specific aim will determine the clinical benefits of passively transferring mouse CD4+ T cells, or subpopulations of CD4+ T cell, into mSOD1 mice. This aim will also determine whether ex vivo expanded CD4+ T cells (such as Treg and Th2 lymphocytes) further enhance survival. Thus, this specific aim will provide proof-of-principle that CD4+ T cells, or subpopulations of CD4+ T cells, are therapeutic candidates for ALS. The 2nd specific aim will determine the clinical benefits of passively transferring ex vivo expanded human CD4+ T cells obtained from ALS patients into immunodeficient mSOD1 mice. This specific aim will provide proof-of-principle that the ALS patient's own CD4+ T cells may be used for therapy. Since ALS patients seek medical attention only after disease onset, therapies directed at slowing disease progression are vitally needed. Therefore, the proposed studies are designed to develop proof-of-principle data on the efficacy of CD4+ T cells, or subpopulations of CD4+ T cells, as a candidate therapy to slow or arrest disease progression. This translational project will lead directly to subsequent projects using CD4+ T cells as a therapy to slow disease progression in ALS patients. PUBLIC HEALTH RELEVANCE: ALS is a horrific, devastating neurodegenerative disease in which patients watch themselves deteriorate over a very short period of time;and despite extensive basic investigations, there is minimal effective therapy Our own efforts to develop meaningful therapies have focused upon the roles of the innate and adaptive immune systems. Recently, T cells have been shown to have the ability to improve neurological function and life expectancy in ALS models. Since T cells are readily accessible in ALS patients, defining the specific populations mediating neuroprotection in the ALS models is translatable into our ultimate goal of using T cell therapies in ALS patients to slow disease progression and improve their quality of life.